Pathogénie du psoriasis

• Une des affections humaines les plus fréquentes– 25 millions de personnes Europe et Amérique

du Nord

• Croissance et différenciation anormale des kératinocytes

• Réversible après thérapeutique appropriée• Génétique et immunologique

– Activation du système immunitaire

2012

• Nature Outlook– After decades of modest advances, psoriasis

research has caught fire. The drug pipeline is full of novel agents. Research into the role of the immune system in this skin disease is bearing fruit. Genetic studies hint at the condition's starting point. And now psoriasis is a proof-of-principle disease for other chronic inflammatory conditions.

image

• Skin, vue d'artiste– Appétissante– Grapes and flakes

Psoriasis

• Maladie auto-immune spécifique d’organe– Déclenchée par activation du système immunitaire– Analogue à

• Maladie de Crohn, RCH (MICI)• Polyarthrite rhumatoïde, • Sclérose en Plaques, • Diabète de type I

– #syndrome clinique causé par activation des cellules T et/ou B, en l’absence d’une infection ou d’une autre cause connue

• Davidson,A N Engl J Med; 2001:345:340

Z

• z

Clinique du psoriasis

• Psoriasis vulgaire– Plaques rouges, surélevées, pseudocicatricielles– Apparition à l’adolescence, ou chez le jeune adulte – et dure toute la vie– Localisations: coudes, genoux, cuir chevelu– Localisé ou généralisé

• Psoriasis en gouttes• Variants: plaques épaisses, ou fines, larges ou

petites• Arthrite psoriasique

Clinique

• Topographie• Epidémiologie

Psoriasis: un modèle?

• Accessibilité de l’organe lésé

• + disponibilité de thérapeutiques immunologiquement actives facilement testées in vivo

• http://dermatlas.med.jhmi.edu/

Peau, cicatrisation

• Image stratum

Figure 2 Schematic representation of keratinocyte phenotypes in acute (A) and chronic (B) wounds Figure 2 Schematic representation of keratinocyte phenotypes in acute (A) and chronic (B) wounds

Biology of the Cell www.biolcell.org Biol. Cell (2006) 97, 173-183 Biology of the Cell www.biolcell.org Biol. Cell (2006) 97, 173-183

Histologie

• Epaississement de l’épiderme– prolifération des kératinocytes dans l’épiderme

interfolliculaire– Allongement des « rete » épidermiques

• Différenciation terminale aberrante des kératinocytes # maturation régénérative, exprimée pendant la cicatrisation

– Réduction majeure de la couche granuleuse de l’épiderme

– Formation de stratum corneum à partir de kératinocytes incomplétement différenciés et gardant leur noyau(parakératose)

– Desquamation et fragilité de la barrière cutanée :• due à l’échec de l’accumulation des kératinocytes, de

secrétion des lipides extracellulaires et d’adhésion

Autres caractéristiques de la peau psoriasique

• Présence de neutrophiles en petits foyers dans le stratum corneum

• Infiltrat mononucléé dans l’épiderme• Infiltrat marqué de cellules mononucléées

(lymphos T et DCs) dans le derme et les vaisseaux du derme papillaire

• Dilatation des vaisseaux… rougeur• Adhérence des L,M,P aux cellules endothéliales

des vx HEV-like• Activation des cellules endothéliales (CD54

ICAM-1, CD106 VCAM-1, CD62E

Lymphocytes (T), PMNs

• local

En résumé

• Peau normale

• Beaucoup de lymphocytes T

• Populations résidentes de DCs– site potentiel de réponses immunitaires

• Peau psoriasique – Tissu lymphoïde organisé– Autoentretien

Cells

Histopathologie du Psoriasis

• http://www.nature.com/nature/journal/v445/n7130/full/445811a.html

Yin et Yang des interactions cellulaires du psoriasis

• Deux acteurs principaux– Keratinocytes épidermiques– Leucocytes mononucléés

• Évolution d’une théorie – où les kératinocytes sont des victimes passives de

l’activation immunitaire– vers celle où ils sont des participants actifs dans le

recrutement et l’activation des leucocytes dans les lésions psoriasiques

• Equilibre– Immunité innée et acquise– Interactions kératinocytes et leucocytes

Psoyinyang

Cellules effectrices de l’immunité innée

• Cellules dendritiques plasmacytoïdes

• Cellules dendritiques CD11c+

• Neutrophiles– Courte durée de vie– Besoin de recrutement régulier depuis le sang– Rôles de chemokines IL-8, GRO- (CXCL1)

Cellules dendritiques

• Cellules de Langerhans, – et DC dermiques

• Cellules dendritiques plasmacytoïdes– BDCA-2, CD123+, – produisant taux élevés d’interféron-– Rôle déclenchant majeur– Autant que de cellules T

Autres DC

• Cellules dendritiques myéloïdes (CD11C+) interstitielles– Taux élevé de TNF, et iNOS

• (équivalent des TIP-DCs qui sont les cellules effectrices pour l ’élimination des infections bactériennes chez la souris)

– IL-23, IL-20 activatrices respectives des T et des kératinocytes

– Une fraction porte des marqueurs de maturation DC-LAMP ou CD83, présentatrices d’Ags

– Agrégats dermiques avec chemokines d’organisation du tissu lymphoïde (CCL19, CCL21, CXCL12, CCL18)

T cells

• Polarisées– TH1 (CD4+) TC1 (CD8+) – TH17 (induites par l’IL-23)– CD8 spécialisées pour le

homing dans l’épiderme (E(CD103)7)

– CD161: rôle des cellules NKT• NKR-P1A, is a C-type lectin

membrane glycoprotein

TH17

• Des DCs • aux TH1,17

Kératinocytes

• Influencent immunité innée– HSPs ou S100A12– TLR agonistes

• Sur immunité spécifique– Populations T clonales?

• Mécanisme??– Persistance antigène– Défaut de fonction des Treg

• Argument expérimental majeur– Réversibilité à l’aide de biothérapies immunologiques

CTLA4Ig, ou DAB389IL-2

Caught in a loop

• triggers

Inflammation: voies moléculaires• Interactions cytokiniques =

type 1– Inducteurs proximaux IL-23, IL-

12– Production d’IFN- et TNF par

cellules T Th1– Activation de gènes sensibles à

l’IFN-, par transduction du signal STAT1

– IL-23 induit une hyperplasie des kératinocytes chez la souris, effet médié par IL-22 produite par TH17

• Modèle utile, – Mais fraction des 1300 gènes

uprégulés dans le psoriasis!!

IL-12

• pathway

IL-23• Schéma• Modèle dermatologique• In addition to the IMQ-induced

psoriasis model launched last year, the most recent model to be validated is the IL-23 induced model of psoriasisform inflammation.

• The IL-23 psoriasis model is 21 days long and involves the injection of IL-23 into the ear of C57Bl/6, which produces psoriasis-like inflammation that is dependent on IL-22. IL-22 induces keratinocyte proliferation and epidermal hyperplasia contributing to epidermal thickening.

• MD Biosciences

Innate immunity

• NF-kB

Schéma = modèle interactif

• STAT1, STAT3 et NF-kB sont activés• Activateurs en amont

– STAT1: interféron– NFkB: IL-1 ou TNF– Mais aussi IL-20 et IL-22

• Cytokines dérivées des kératinocytes PDGF

• VEGF– Induisent croissance des kératinocytes

Interactions

• Cellules stromales produisent KGF (keratinocyte growth factor) 1ou 2?

• Cytokines régulent prolifération kératinocytaires– (+) IL-1, 6, 17, 19, 20, 22, TNF, IFNs– (-) /blocage TNF, IL-12, ou IL-23

– TGF bêta? Surexprimé de façon focale dans la peau du psoriasis (Journal of Investigative Dermatology (2001) 117, 569–

575)

Animal model/mutated mice Nature asia 2012

• Xiaoxia Li and colleagues report that the dysregulation of IL-17 signaling in TH17 cells contributes to disease.

• They use a disease model of psoriasis in mice harboring a specific mutation in Act1, protein that interacts with the IL-17 receptor and for which there is known mutation that is also associated with human disease.

• Normally IL-17 signaling triggers a self-limiting inflammatory response, but Act1 mutant mice spontaneously develop chronic skin inflammation.

• The authors find mutant Act1 fails to associate with a chaperone protein hsp90, which would cease the inflammatory response. As a result, TH17 cells cannot turn off production of IL-22.

• The authors found that blocking IL-22 with neutralizing antibodies alleviated skin disease in the mutant mice. These findings suggest that anti-IL-22 therapies might be beneficial to those patients that express defective Act1.

Psoriasis et cytokines

Facteurs génétiques

• Maladie des caucasiens (1-2%), vs asiatiques (0.1%), africains (rares)

• Maladie multigénique– 10-20 régions chromosomiques ?– Peu de gènes candidats– Peu de familles étudiées

• MHC classe I– Pénétrance faible (10%)– Gène de susceptibilité PSORS1?– Association avec Cw6, > 25 years– Corneodesmosin?, HCR a-helical coil-coil rod

Autres gènes

• Du système immunitaire ou des kératinocytes– Immune synapse

• SLC9A3R1/NAT9 region… RUNX binding site • Lymphoid phosphatase• Associations IL-12, IL-19/20, IRF2

– EDC epidermal differenciation complex…– Mendelien: 17q25

• Autosomal dominant• Zinc finger protein ZNF750 keratinocytes, pas fibroblastes ni

CD4 T cells

Nature Genetics 2012metaanalysis

• 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals.

• also identified, using conditional analyses, five independent signals within previously known loci.

• The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3).

• Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1).

Modèles animaux??

• Homme différent des animaux à fourrure!– Plus d’épiderme interfolliculaire (entre

follicules pileux)… psoriasis, eczéma atopique

• Pas de modèle spontané

• Engineering cutané

• Xénotransplantation

pathogénie

• Y/Y

Microbiome

• 2012• 2013• … psoriasis induces

physiological changes both at the lesion site and at the systemic level, which select for specific differential microbiota among the assayed clinical skin types. These differences in microbial community structure in psoriasis patients are potentially of pathophysiologic and diagnostic significance.

Once upon a time

• Therapies

Psoriasis et Biothérapies

Etudes cliniques, preuve de concept

• Biothérapies approuvées au cours des 3 dernières années! Pour le psoriasis sévère

• Protéines ou anticorps ciblant des molécules spécifiques essentielles pour la pathogénie de la maladie

• Deux cibles – Médiateurs de l’inflammation– Cellules T

• Risque d’immunosuppression, – infections, cancers

• Bien tolérées mais …? recul

Classification 4 groupes

• Produits (approuvés dans d’autres indications) utilisés dans des études antérieures utiles pour établir le substrat immunologique du psoriasis

• Immunosuppresseurs systémiques classiques• Nouvelles biothérapies récemment approuvées

USA, Europe• Thérapeutiques prometteuses encore en

développement

Agents soutenant le concept immunologique du psoriasis

• Tacrolimus/FK506 PROGRAF– Calcineurin (protein phosphatase 2B)

• Anticorps monoclonaux– CD25

• Ontak DAB389IL-2 (toxique)• Daclizumab (Zenepax)• Basiliximab (Simulect)

– CD80/CD86• Abatacept (CTLA4Ig) (Orencia)

Différenciation kératinocytes

• Inhibiteurs de calcineurine

Médicaments largement utilisés

• Methotrexate (Rheumatrex, Trexall)– Leucocytes

• Tacrolimus• Cyclosporine (Neoral, Gengraf)

– Calcineurin

• Fumarates (Germany)– T cells

Biothérapies récemment approuvées

• Cible TNF, lymphotoxin– Infliximab (Remicade) FDA, EMEA

• Anticorps monoclonal chimérique humain liant TNF libre et lié

– Etanercept (Enbrel) FDA, EMEA• TNF receptor et Ig fusion liant TNF et lymphotoxinalpha

– Efficacité impressionnante mais variable selon traitement

– Hospira's Inflectra? (infliximab) the first biosimilar monoclonal antibody to receive positive opinion from EMA's CHMP for rheumatoid arthritis, inflammatory bowel disease and plaque psoriasis - Appli

Biothérapies en investigations et cibles

• Calcineurin– Pimecrolimus (Elidel-topique eczéma)

• TNF– Adalimumab (FDA arthrite psoriasique) HUMIRA– Premier anticorps recombinant humain

théoriquement semblable à l’infliximab– Protocole suivi Researchers observed antidrug

antibody in 49% of patients during the extension study, with 90% of them displaying ADA formation by week 24.

– Hospira's Inflectra? (infliximab) the first biosimilar monoclonal antibody to receive positive opinion from EMA's CHMP for rheumatoid arthritis, inflammatory bowel disease and plaque psoriasis - Appli

ADA• Antidrug antibodies (ADAs) against biological agents may be clinically significant and potentially

alter a biological drug's treatment efficacy. • This systematic review aims to

– (i) determine the prevalence of ADAs against infliximab, etanercept, adalimumab and ustekinumab in patients with psoriasis;

– (ii) ascertain whether ADAs are associated with changes in drug efficacy; and (iii) explore the use of concomitant methotrexate to prevent ADA formation.

• Through a systematic search using Medline and Embase from 29 January 1950 to 29 March 2013, we identified 25 studies that met the inclusion criteria.

• Of 7969 patients with psoriasis, 950 tested positive for ADAs. Antibodies against infliximab, etanercept, adalimumab and ustekinumab were reported in 5·4–43·6%, 0–18·3%, 6–45% and 3·8–6% of patients, respectively.

• Anti-infliximab antibodies were associated with lower serum infliximab concentrations in three studies, and decreased treatment response in five studies.

• ADAs against etanercept were non-neutralizing and not associated with any apparent effects on clinical response.

• Antiadalimumab antibodies were associated with lower serum adalimumab concentrations in three of five studies, and reduced clinical efficacy in four studies.

• Two of six studies reported that antiustekinumab antibodies were associated with lower Psoriasis Area and Severity Index responses, and three ustekinumab studies noted that most of these antibodies were neutralizing.

• Although the use of concomitant methotrexate with biological agents to prevent ADA formation in other immune-mediated diseases is promising, their use in psoriasis is sparse.

• ADA development remains a challenge with biological therapies and therefore should be considered in patients with psoriasis who experience diminished treatment response.

• British Journal of Dermatology• Volume 170, Issue 2, pages 261–273, February 2014

Nature

• 2012

Cible CD11a

• Cible CD11a (LFA-1)– Efalizumab (Raptiva) FDA, EMEA– Ciblé adhésion et costimulation– Actif dans sous groupe de psoriasis sévère, mais

nécessite traitement au long cours

– Anticorps monoclonal murin humanisé ciblant CD11a– CD11a:CD18 lien ICAM-1 et -2– Génération initiale de la réponse immune dans les

ganglions et dans la peau entre migration cellules T, activation et entrée dans épiderme

– Entraîne leucocytose sanguine CD8 mémoire, par blocage interaction LFA-1 ICAM-1

– diminution des CD11c+ TIP DCs

CD2

• Cible CD2 – Alefacept (Amevive) FDA– Protéine de fusion contenant le domaine

extracellulaire de CD58 (LFA-3)– Cible cellules T, NK, qq DC CD14+– Mécanisme, diminution des T, apoptose des

cellules T?– Diminution des DCs CD11C et CD83– Diminution de gènes IFN, STAT1, iNOS, IL-8,

IL-23, IL-20

CD4

• Tregalizumab (BT-061):• Tregalizumab enhances a natural mechanism of

down regulating excessive immune responses and is therefore developed to treat disease conditions that originate from an overreaction of the immune system.

• “Tregalizumab is a humanized, agonistic monoclonal antibody which binds to a unique epitope of CD4, and induces Treg-specific activation and suppresses CD4 and CD8 effector cell proliferation and activity in vitro.”

CD6

• Itlizumab, premier anticorps humanisé (BIOCON)

• Itolizumab, the first humanized anti CD-6 monoclonal antibody, successfully met the pre-specified primary endpoint of significant improvement in PASI-75 (Psoriasis Area and Severity Index) score after 12 weeks of treatment in patients with moderate to severe psoriasis compared to placebo. It also met multiple secondary endpoints after 12 and 28 weeks of treatment.

Cell therapies: anti-peptide

• There are several compelling lines of evidence for T cell involvement in psoriasis, including the initiation of psoriatic lesions in immunodeficient mice after transfer of superantigen or IL-2 activated peripheral blood leukocytes from psoriasis patients. In addition, intra-epidermal CD8+ T cells isolated from plaque regions were found to be oligoclonal, expressing BV3 and BV13S1 genes in their TCRs

• Zorcell Psoriasis Phase II Vaccine Multicenter Study Double Blind Placebo and Adjuvant-Controlled Trial of TCR Peptide Vaccination in Psoriasis VulgarisUsing a Combination of BV3 and BV13S1 20 mer or 40 mer CDR2 peptides (Gottlieb et al. in Preparation)

BTLA

• How BTLA is regulated• Using a combination of human cells and a mouse

model of psoriasis, the research team described a new pathway that regulates BTLA expression. Ware's research showed that the "retinoid-related orphan receptor gamma-t" (ROR gamma-t) nuclear transcription factor works with interleukin (IL)-7, to coordinate the expression of BTLA, which in turn regulates gamma-delta T cell responses to inflammatory stimuli.

• The study found that ROR gamma-t works to inhibit BTLA transcription, thereby limiting its availability in gamma-delta T-cells. This allows the expansion of T-cell numbers and their production of inflammatory cytokines, including IL-17 and TNF.

Antagonistes immunologiques ciblés

• Intérêt avec analyse cellulaire, moléculaire des voies d’activation – Exemple:

• Etanercept effets… suggèrent que TNF régule IL-1 et IL-8 mais plus complexe sur voies d’activation

• JAK inhibitors• Bone Marrow transplantation?

– J Am Acad Dermatol. 2013 Mar;68(3):489-92. doi: 10.1016/j.jaad.2012.08.021. Epub 2012 Sep 12.

– Remission of psoriasis after allogeneic, but not autologous, hematopoietic stem-cell transplantation.

JAK inhibitors

• Janssen has acquired immunology rights to Astellas' oral Janus Kinase (JAK) inhibitor ASP015K, which has completed phase IIa trials for plaque psoriasis and is currently in phase IIb for rheumatoid arthritis.

• But the agreement only covers ASP015K as an oral treatment for immune-mediated inflammatory diseases.

• Meanwhile, Pfizer's tofacitinib is on-track to become the first JAK inhibitor to reach the market for rheumatoid arthritis.

• Tyrosine kinase 2 (Tyk2), a member of the Jak kinase family, mediates signals triggered by various cytokines, which are related to the pathogenesis of psoriasis. Int. Immunol. (2013) doi: 10.1093/intimm/dxt062

IL-12…

• IL-12– Cent-1275– ABT-874

• IL-15 (#IL-2)– 146B7

IL-17• Ixekizumab (Eli Lilly)• New England 2012:

– At 12 weeks, the percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab (except with the lowest, 10-mg dose) — 150 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%) — than with placebo (7.7%, P<0.001 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25 mg (50.0%) versus placebo (0%, P<0.001 for each comparison).

– Similarly, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%) (P<0.001 for both comparisons).

– Significant differences occurred at as early as 1 week and were sustained through 20 weeks. Adverse events occurred in 63% of patients in both the combined ixekizumab groups and in the placebo group. No serious adverse events or major cardiovascular events were observed.

IL-17R

• Brodalumab• NEJM 2012

IL-22• Cytokines are critical checkpoints of inflammation. The treatment of human autoimmune disease

has been revolutionized by targeting inflammatory cytokines as key drivers of disease pathogenesis. Despite this, there exist numerous pitfalls when translating preclinical data into the clinic.

• We developed an integrative biology approach combining human disease transcriptome data sets with clinically relevant in vivo models in an attempt to bridge this translational gap.

• We chose interleukin-22 (IL-22) as a model cytokine because of its potentially important proinflammatory role in epithelial tissues. Injection of IL-22 into normal human skin grafts produced marked inflammatory skin changes resembling human psoriasis. Injection of anti–IL-22 monoclonal antibody in a human xenotransplant model of psoriasis, developed specifically to test potential therapeutic candidates, efficiently blocked skin inflammation. Bioinformatic analysis integrating both the IL-22 and anti–IL-22 cytokine transcriptomes and mapping them onto a psoriasis disease gene coexpression network identified key cytokine-dependent hub genes.

• Using knockout mice and small-molecule blockade, we show that one of these hub genes, the so far unexplored serine/threonine kinase PIM1, is a critical checkpoint for human skin inflammation and potential future therapeutic target in psoriasis.

• Using in silico integration of human data sets and biological models, we were able to identify a new target in the treatment of psoriasis.

• Sci Transl Med 12 February 2014: Vol. 6, Issue 223, p. 223ra22 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3007217

Ciblage IL-23

• Guzelkumab• X-PLORE, a Phase 2b, randomized, placebo-

and active comparator-controlled, parallel-group, multicenter dose-ranging study, investigated subcutaneous injections of five doses of guselkumab compared with placebo and adalimumab in patients with moderate to severe plaque psoriasis, defined by a PASI greater than or equal to 12, PGA greater than or equal to 3 and body surface area (BSA) involvement of at least 10 percent who are candidates for systemic or phototherapy

p40IL-12/IL-23!

• Ustekinumab (STELARA)– Efficacy and safety of ustekinumab in patients with active

psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet

– But– Inhibition progression articulaire, mais discuté approuvé FDA,

refusé NICE (cost effectiveness)– Psoriasis patients experienced arthritis flares following

ustekinumab treatment

• Briakinumab anti-p40– Briakinumab showed higher efficacy than methotrexate in

patients with moderate-to-severe psoriasis. Serious infections and cancers occurred more frequently with briakinumab, NEJM 2011

microRNA

• The anti-miR-21 molecules are tiny strands of nucleotides that specifically glom onto miR-21 and prevent it from functioning.

• Wagner and his colleagues injected this treatment into the skin of mice bearing grafts of diseased tissue from human patients with psoriasis.

• The anti-miR-21 reduced the thickness of the human skin lesions by about half, a response similar to that obtained using the antibody-based psoriasis therapy etanercept (commercially available from California-based Amgen as Enbrel).

Topical treatments

• Thermalisme• Phototherapy UV• Alternative, complementary therapies,

ayurvedic!• To• Il-8 cream• a topical formulation of a gene-regulating

nanoparticle (Dual-F-NALP) carrying two nucleic acids, which controls the skin cells from developing psoriatic plaques and suppresses inflammation.

Nature video sur Youtubehttp://www.youtube.com/watch?v=_VhcZTGv0CU#t=412

7’29• The skin is the body's main barrier against physical

insults and microbial pathogens. Diverse and functionally specialized subsets of immune cells in the skin sense and respond to infection or various barrier breaches to activate an immune response and eventually, return to homeostasis. However, deregulated immune responses can also cause skin disorders, such as psoriasis.

This Nature Video introduces the environment and key participants in skin immunity during steady-state and disease.

X

• Y

En résumé

• Pathologie simplifiée, comparer avec dia 11

• October 29 is Psoriasis day

Acknowledgments

• Nature 2012

• Scoop.it– Out of immunology

and biothérapies– Out of immunology